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https://www.readbyqxmd.com/read/29780994/molecular-mechanism-of-15-lipoxygenase-allosteric-activation-and-inhibition
#1
Hu Meng, Ziwei Dai, Weilin Zhang, Ying Liu, Luhua Lai
Human reticulocyte 15-lipoxygenase (15-LOX) plays an important role in inflammation resolution and is also involved in many cancer-related processes. Both an activator and an inhibitor will serve as research tools for understanding the biological functions of 15-LOX and provide opportunities for drug discovery. In a previous study, both allosteric activators and inhibitors of 15-LOX were discovered through a virtual screening based computational approach. However, why molecules binding to the same site causes different effects remains to be disclosed...
May 21, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29772700/inhibition-of-arachidonate-12-15-lipoxygenase-improves-%C3%AE-galactosidase-efficacy-in-ipsc-derived-cardiomyocytes-from-fabry-patients
#2
Yueh Chien, Shih-Jie Chou, Yuh-Lih Chang, Hsin-Bang Leu, Yi-Ping Yang, Ping-Hsing Tsai, Ying-Hsiu Lai, Kuan-Hsuan Chen, Wei-Chao Chang, Shih-Hsien Sung, Wen-Chung Yu
(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In this study, we constructed an induced pluripotent stem cell (iPSC)-based platform from Fabry cardiomyopathy (FC) patients carrying IVS4+919 G>A mutation to screen for potential targets that may help the conventional treatment; (3) Results: The FC-patient-derived iPSC-differentiated cardiomyocytes (FC-iPSC-CMs) carried an expected IVS4+919 G>A genetic mutation and recapitulated several FC characteristics, including low α-galactosidase A enzyme activity and cellular hypertrophy...
May 16, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29763661/prominent-release-of-lipoxygenase-generated-mediators-in-a-murine-house-dust-mite-induced-asthma-model
#3
Johan Kolmert, Sergio Piñeiro-Hermida, Craig E Wheelock, Mats Hamberg, Joshua A Gregory, Icíar P López, Alexander Fauland, Sven-Erik Dahlén, José G Pichel, Mikael Adner
The profile of activation of lipid mediator (LM) pathways in asthmatic airway inflammation remains unclear. This experimental study quantified metabolite levels of ω3-, ω6- and ω9-derived polyunsaturated fatty acids in bronchoalveolar lavage fluid (BALF) after 4-weeks of repeated house dust mite (HDM) exposure in a murine (C57BL/6) asthma model. The challenge induced airway hyperresponsiveness, pulmonary eosinophil infiltration, but with low and unchanged mast cell numbers. Of the 112 screened LMs, 26 were increased between 2 to >25-fold in BALF with HDM treatment (p < 0...
May 12, 2018: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/29763636/inhibition-of-cox-2-mpges-1-and-5-lox-in-macrophages-by-leonurine-ameliorates-monosodium-urate-crystal-induced-inflammation
#4
Yanzhuo Liu, Chenfan Duan, Honglei Chen, Chenlong Wang, Xiaoxiao Liu, Miao Qiu, Honglin Tang, Feng Zhang, Xiaoyang Zhou, Jing Yang
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) in the synovial fluid macrophages...
May 15, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29760648/profile-of-arachidonic-acid-derived-inflammatory-markers-and-its-modulation-by-nitro-oleic-acid-in-an-inherited-model-of-amyotrophic-lateral-sclerosis
#5
Andrés Trostchansky, Mauricio Mastrogiovanni, Ernesto Miquel, Sebastián Rodríguez-Bottero, Laura Martínez-Palma, Patricia Cassina, Homero Rubbo
The lack of current treatments for amyotrophic lateral sclerosis (ALS) highlights the need of a comprehensive understanding of the biological mechanisms of the disease. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected as a screening tool to identify treatment response. Herein, we focus on (a) detection of arachidonic acid (AA) metabolization products by lipoxygenase (LOX) and prostaglandin endoperoxide H synthase in SOD1G93A mice and (b) evaluate its response to the electrophilic nitro-oleic acid (NO2 -OA)...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29759936/in-vitro-antioxidant-antilipoxygenase-and-antimicrobial-activities-of-extracts-from-seven-climbing-plants-belonging-to-the-bignoniaceae
#6
Carola Analía Torres, Cristina Marisel Pérez Zamora, María Beatriz Nuñez, Ana María Gonzalez
OBJECTIVES: This study aimed to evaluate the in vitro antioxidant capacity, to determine the anti-inflammatory effect due to lipoxygenase inhibition and to test the antimicrobial activity of ethanolic extracts from leaves of seven climbing species belonging to the Bignoniaceae family. These species are Adenocalymma marginatum (Cham.) DC., Amphilophium vauthieri DC., Cuspidaria convoluta (Vell.) A. H. Gentry, Dolichandra dentata (K. Schum.) L. G. Lohmann, Fridericia caudigera (S. Moore) L...
May 3, 2018: Journal of Integrative Medicine
https://www.readbyqxmd.com/read/29758943/novel-key-players-in-the-development-of-tau-neuropathology-focus-on-the-5-lipoxygenase
#7
Elisabetta Lauretti, Domenico Praticò
Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss...
May 11, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29750575/unified-nexus-of-macrophages-and-maresins-in-cardiac-reparative-mechanisms
#8
Jeevan Kumar Jadapalli, Ganesh V Halade
Macrophages are immune-sensing "big eater" phagocytic cells responsible for an innate, adaptive, and regenerative response. After myocardial infarction, macrophages predominantly clear the deceased cardiomyocyte apoptotic or necrotic neutrophils to develop a regenerative and reparative program with the activation of the lipoxygenase-mediated maresin (MaR) metabolome at the site of ischemic injury. The specialized proresolving molecule and macrophage mediator in resolving inflammation, MaR-1, produced by human macrophages, has potent defining effects that limit polymorphonuclear neutrophil infiltration, enhance uptake of apoptotic PMNs, regulate inflammation resolution and tissue regeneration, and reduce pain...
May 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29739755/erv1-chemr23-signaling-protects-from-atherosclerosis-by-modifying-oxldl-uptake-and-phagocytosis-in-macrophages
#9
Andres Laguna-Fernandez, Antonio Checa, Miguel Carracedo, Gonzalo Artiach, Marcelo H Petri, Roland Baumgartner, Maria J Forteza, Xintong Jiang, Teodora Andonova, Mary E Walker, Jesmond Dalli, Hildur Arnardottir, Anton Gisterå, Silke Thul, Craig E Wheelock, Gabrielle Paulsson-Berne, Daniel F J Ketelhuth, Göran K Hansson, Magnus Bäck
Background -In addition to enhanced pro-inflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Pro-resolving lipid mediators formed through the 12/15 lipoxygenase pathways exert protective effects against murine atherosclerosis. n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), serve as the substrate for the formation of lipid mediators, which transduce potent anti-inflammatory and pro-resolving actions through their cognate G-protein-coupled receptors...
May 8, 2018: Circulation
https://www.readbyqxmd.com/read/29736687/cyclooxygenase-and-lipoxygenase-gene-expression-in-the-inflammogenesis-of-breast-cancer
#10
Brian M Kennedy, Randall E Harris
We examined the expression of major inflammatory genes, cyclooxygenase-1 and 2 (COX1, COX2) and arachidonate 5-lipoxygenase (ALOX5) in 1090 tumor samples of invasive breast cancer from The Cancer Genome Atlas (TCGA). Mean cyclooxygenase expression (COX1 + COX2) ranked in the upper 99th percentile of all 20,531 genes and surprisingly, the mean expression of COX1 was more than tenfold higher than COX2. Highly significant correlations were observed between COX2 with eight tumor-promoting genes (EGR2, IL6, RGS2, B3GNT5, SGK1, SLC2A3, SFRP1 and ETS2) and between ALOX5 and ten tumor promoter genes (CD33, MYOF1, NLRP1, GAB3, CD4, IFR8, CYTH4, BTK, FGR, CD37)...
May 7, 2018: Inflammopharmacology
https://www.readbyqxmd.com/read/29733849/dexmedetomidine-restores-septic-renal-function-via-promoting-inflammation-resolution-in-a-rat-sepsis-model
#11
Rongzong Qiu, Weifeng Yao, Haocong Ji, Dongdong Yuan, Xiaofeng Gao, Weiping Sha, Fei Wang, Pinjie Huang, Ziqing Hei
BACKGROUND: Acute kidney injury occurred after sepsis, resulting in high mortality. This research aims to elucidate the mechanistic effect of DEX on the renal inflammation resolution during sepsis in rats. METHODS: The rats were randomly divided into a sham group and the other three cecal ligation and puncture (CLP) model groups, based on different treatments: placebo, DEX and 2-adrenergic receptor (AR) inhibitor atipamezole (AT) treatment (DEX + AT) groups...
May 4, 2018: Life Sciences
https://www.readbyqxmd.com/read/29732612/synthesis-of-substituted-fluorobenzimidazoles-as-inhibitors-of-5-lipoxygenase-and-soluble-epoxide-hydrolase-for-anti-inflammatory-activity
#12
B Nandha, Sureshbabu A Ramareddy, Hazra Kuntal
A new series of 4-((5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)methyl)-benzoic acids 4a-o and 2-(5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)-2-methylpropanoic acids 8a-e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX) were investigated. These molecules were designed based on the combination of 5-LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5-LOX inhibitory activity. Compound 4g showed remarkable activity with IC50 values of less than 1 μM (0...
May 7, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29731704/oxytosis-ferroptosis-re-emerging-roles-for-oxidative-stress-dependent-non-apoptotic-cell-death-in-diseases-of-the-central-nervous-system
#13
REVIEW
Jan Lewerenz, Gamze Ates, Axel Methner, Marcus Conrad, Pamela Maher
Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29728702/elevated-levels-of-brain-homocysteine-directly-modulate-the-pathological-phenotype-of-a-mouse-model-of-tauopathy
#14
Antonio Di Meco, Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy...
May 4, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29727733/lipophilic-extracts-of-leucas-zeylanica-a-multi-purpose-medicinal-plant-in-the-tropics-inhibit-key-enzymes-involved-in-inflammation-and-gout
#15
Mayuri Napagoda, Jana Gerstmeier, Hannah Butschek, Sybille Lorenz, Dinusha Kanatiwela, Sudhara De Soyza, Mallique Qader, Ajith Nagahawatte, Gaya Bandara Wijayaratne, Aleš Svatoš, Lalith Jayasinghe, Andreas Koeberle, Oliver Werz
ETHNOPHARMACOLOGICAL RELEVANCE: Leucas zeylanica (L.) W.T. Aiton is a popular, multi-purpose medicinal plant in Sri Lanka but the pharmacological potential and the chemical profile have not been systematically investigated to understand and rationalize the reported ethnobotanical significance. AIM OF THE STUDY: The present study was undertaken to scientifically validate the traditional usage of this plant for the treatment of inflammatory conditions, gout and microbial infections...
May 1, 2018: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29726968/characterization-and-alternative-splicing-profiles-of-lipoxygenase-gene-family-in-tea-plant-camellia-sinensis
#16
Junyan Zhu, Xuewen Wang, Lingxiao Guo, Qingshan Xu, Shiqi Zhao, Fangdong Li, Xiaomei Yan, Shengrui Liu, Chaoling Wei
Oxylipins, including jasmonic acid (JA) and volatiles, are important for signaling in plants, and these are formed by the Lipoxygenases (LOX) enzyme family. There is a large gap in understanding of the underlying molecular basis of their roles in tea plants. Here, we identified eleven CsLOX genes from tea plant (Camellia sinensis), and characterized their phylogeny, gene structure and protein features into three subclasses. We then examined their enzymatic activities, LOX expression and alternative splicing of transcripts during development and in response to abiotic or biotic stresses in tea plants...
May 2, 2018: Plant & Cell Physiology
https://www.readbyqxmd.com/read/29708818/a-placebo-controlled-double-blind-study-demonstrates-the-clinical-efficacy-of-a-novel-herbal-formulation-for-relieving-joint-discomfort-in-human-subjects-with-osteoarthritis-of-knee
#17
Vasu Karlapudi, Anjaneya Venkata Vara Prasad Mungara, Krishanu Sengupta, Barbara A Davis, Siba Prasad Raychaudhuri
LI73014F2 is a novel composition prepared from extracts of Terminalia chebula fruit, Curcuma longa rhizome, and Boswellia serrata gum resin with synergistic benefit in 5-Lipoxygenase (5-LOX) inhibition. This herbal composition with strong anti-5-LOX activity exhibited significant pain relief as indicated through improvements in weight-bearing capacity in a monosodium iodoacetate-induced osteoarthritis (OA) model of Sprague-Dawley rats. A 90-day randomized, placebo-controlled double-blind study evaluates the clinical efficacy and tolerability of LI73014F2 in the management of symptoms of OA of the knee (Clinical Trial Registration No...
April 30, 2018: Journal of Medicinal Food
https://www.readbyqxmd.com/read/29702245/female-mice-carrying-a-defective-alox15-gene-are-protected-from-experimental-colitis-via-sustained-maintenance-of-the-intestinal-epithelial-barrier-function
#18
Saskia Kroschwald, Cheng-Ying Chiu, Dagmar Heydeck, Nadine Rohwer, Tatjana Gehring, Ulrike Seifert, Anke Lux, Michael Rothe, Karsten-Henrich Weylandt, Hartmut Kuhn
Lipoxygenases (ALOX) are involved in the regulation of cellular redox homeostasis. They also have been implicated in the biosynthesis of pro- and anti-inflammatory lipid mediators and play a role in the pathogenesis of inflammatory diseases, which constitute a major health challenge owing to increasing incidence and prevalence in all industrialized countries around the world. To explore the pathophysiological role of Alox15 (leukocyte-type 12-LOX) in mouse experimental colitis we tested the impact of systemic inactivation of the Alox15 gene on the extent of dextrane sulfate sodium (DSS) colitis...
April 24, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29698924/integrative-metabolomics-and-transcriptomics-signatures-of-clinical-tolerance-to-plasmodium-vivax-reveal-activation-of-innate-cell-immunity-and-t-cell-signaling
#19
Luiz G Gardinassi, Myriam Arévalo-Herrera, Sócrates Herrera, Regina J Cordy, ViLinh Tran, Matthew R Smith, Michelle S Johnson, Balu Chacko, Ken H Liu, Victor M Darley-Usmar, Young-Mi Go, Dean P Jones, Mary R Galinski, Shuzhao Li
Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P...
April 11, 2018: Redox Biology
https://www.readbyqxmd.com/read/29698923/anti-inflammatory-effects-of-%C3%AE-linolenic-acid-in-m1-like-macrophages-are-associated-with-enhanced-production-of-oxylipins-from-%C3%AE-linolenic-and-linoleic-acid
#20
Samantha D Pauls, Lisa A Rodway, Tanja Winter, Carla G Taylor, Peter Zahradka, Harold M Aukema
Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA α-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion...
April 3, 2018: Journal of Nutritional Biochemistry
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